# Multiethnic genomic epigenomic and transcriptomic fine-mapping and functional validation analysis of schizophrenia and bipolar disorder risk loci

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $1,259,821

## Abstract

PROJECT SUMMARY
Serious mental illness (SMI) that includes schizophrenia (SCZ) and bipolar disorder (BD) are common, complex
and debilitating psychiatric disorders that together affect over 2% of the population and carry considerable
morbidity, mortality, and personal and societal cost. Over the last decade, large-scale genome wide association
studies (GWAS) have identified hundreds of loci contributing to the risk of SCZ and BD. Advancing these
statistical associations to causal mechanisms for SMIs is very challenging due to incomplete understanding of
the non-coding regulatory mechanisms in the human brain tissue and the local correlation of risk variants.
Therefore, a systematic analysis that performs fine-mapping to jointly identify and validate a credible set of causal
variants in SMI and molecular features that includes transcripts and regulatory sequences, in relevant tissues
and cell types is a critical next step. The overarching goal of our proposal is to leverage genomics and multiscale
functional omics (gene expression and epigenome regulation) data and perform fine mapping to detect and
validate causal variants, transcripts and regulatory sequences in SMI. In Aim 1, we will perform large-scale trans-
ancestry GWAS of SCZ and BD to expand the current repertoire of risk (and resilience) loci and refine the
credible sets of causal variants underlying genome-wide significant associations. In Aim 2, we will integrate
putative causal variants with multiscale functional omics data from human brain tissue that capture gene
expression and epigenome regulation at the bulk, cell type-specific and single cell level to identify credible sets
of transcripts and regulatory sequences. In Aim 3, we will functionally validate putative causal variants and
regulatory sequences, by using novel approaches that combine massively parallel reporter assays and genome
editing in excitatory and inhibitory neurons derived from human induced pluripotent stem cells. Our computational
and experimental aims bridge the gap between the fine-mapping of causal variants, the molecular gene-
regulatory effects of risk variants on enhancer activity and gene expression and their biological effects at the
cellular level. If successful, our project can elucidate the genes, pathways, and mechanisms underlying SCZ and
BD, and provide new insights and avenues for therapeutic development.

## Key facts

- **NIH application ID:** 10734047
- **Project number:** 5R01MH125246-04
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Panagiotis Roussos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,259,821
- **Award type:** 5
- **Project period:** 2021-01-01 → 2025-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10734047

## Citation

> US National Institutes of Health, RePORTER application 10734047, Multiethnic genomic epigenomic and transcriptomic fine-mapping and functional validation analysis of schizophrenia and bipolar disorder risk loci (5R01MH125246-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10734047. Licensed CC0.

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